The invention herein is directed to the preparation of a compound of the formula ##STR2## using reagents and reaction conditions which are beneficial in comparison to previously disclosed methodology. This compound is useful in the preparation of the platelet aggregation inhibitor, GP IIb/III antagonist, orbofiban.
Orbofiban is an antiplatelet pharmaceutical agent of the formula ##STR3## disclosed in U.S. Pat. No. 5,721,366. A process for making orbofiban is disclosed therein.
A process for preparing an intermediate of the formula ##STR4## is disclosed in U.S. Pat. No. 5,484,946. It is further disclosed therein that the intermediate is useful in the preparation of ethyl 3-[[[[1-[4-(aminoiminomethyl)phenyl]-2-oxo-3(S)-pyrrolidinyl]amino]carbony l]amino]-propionate acetate, also known as orbofiban. The process disclosed therein is for producing a lactam of the formula ##STR5## wherein R is a protecting group such as t-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ) and Z is H, --CN, --CONH.sub.2 or CO.sub.2 alkyl from a methionine analog of the formula ##STR6## by treating the methionine analog with trimethylsulfonium halide or trimethylsulfoxonium halide (such as trimethylsulfonium iodide or trimethylsulfoxonium chloride) in the presence of an inorganic or aminergic base in a suitable aprotic solvent.
The process disclosed therein further provides for dehydrating the lactam so produced when Z is --CONH.sub.2 and deprotecting the lactam, reacting the resulting product with a .beta.-amino ester in the presence of CDI to produce a urea of the formula ##STR7## treating the urea with hydroxylamine to produce an aminodoxime, hydrogenating the amidoxime; and isolating a compound of the formula ##STR8## wherein R.sub.1 is hydrogen, alkyl, aryl, arylalkyl, a heterocyclyl radical containing 1 to 3 heteroatoms or a heterocyclylalkyl and R.sub.6 is selected from alkyl, aryl, arylalkyl or acyloxymethyl.
The process disclosed herein provides an efficient, scalable and cost effective synthesis of the intermediate (3S)-3-amino-1-(4-cyanophenyl)-2-oxopyrrolidine hydrochloride. The present process is advantageous over the process disclosed in U.S. Pat. No. 5,484,946 in that the process disclosed in U.S. Pat. No. 5,484,946 involved the coupling and acylization of a methionine residue which generated a great amount of dimethylsulfide. The cost associated with the waste handling of this by-product made the process unsuitable on a manufacturing scale. The presently disclosed process was designed to overcome this problem.